A NIH study has identified an enzyme GALNT1 that affects function of the spike protein and consequently the infectivity of SARS-CoV-2. Published in the Proceedings of the National Academy of Sciences, the study also states that the mutations in the alpha and delta variants overcome the effect of this enzyme, enhancing their spread. ^1,2

The SARS-CoV-2 binds to and enters the host cells via the spike (S) protein after furin cleavage at the S1/S2 junction and S2. It has been hypothesised that furin cleavage of S is regulated by host cell O-glycosylation, which occurs close to the furin cleavage site and is catalyzed by enzymes known as the UDP-Gal-NAc:polypeptide N-acetylgalactosaminyltransferases (GALNTs). The process of O-glycosylation is dependent on proline (P681), which is present adjacent to the sites of O-glycosylation and furin cleavage.

An experimental study was conducted in fruit fly and mammalian cells to examine the effect of the enzyme GALNT on the spike protein. Results showed that GALNT1 reduces furin cleavage by adding sugars to wild-type spike protein. On the other hand, spike protein mutations reduce activity of GALNT1 and increase furin cleavage. These observations suggest that GALNT1 activity may partially suppress furin cleavage in wild-type virus, but the alpha and delta variants overpower this activity, allowing unrestrained furin cleavage making it easier for the virus to enter into the cells.

In another experiment, it was found that cells expressing mutated spike protein fused with neighbors to a greater extent compared to cells with the wild-type version facilitating transmission of the virus during the infection. “Cells with wild-type spike also fused less in the presence of GALNT1, suggesting that its activity may limit spike protein function”. The O-glycosylation by the GALNT1 enzyme decreases furin cleavage of spike protein and also decreases syncytia formation. ACE2 cells in the lower and upper respiratory tracts in healthy human volunteers were found to extensively express GALNT1.

Kelly Ten Hagen, PhD, a senior investigator at NIH’s National Institute of Dental and Craniofacial Research (NIDCR) and who led the study said, “This study suggests that GALNT1 activity may modulate viral infectivity and provides insight into how mutations in the alpha and delta variants may influence this.”

This study has brought us one step closer to understanding how SARS-CoV-2 infects the host cells. It suggests that the furin cleavage site may be instrumental in spread of infection among humans. O-glycosylation, modulated by GALNT enzymes, specifically GALNT1, decreases furin cleavage and reduces infectivity. Mutations in P681, found in the alpha and delta variants, stop the activity of GALNT1 and decrease O-glycosylation thereby enhancing furin cleavage, increasing syncytia formation and increasing infectivity of the virus. The authors further suggest that GALNTs may be expressed differently in individuals thereby variably affecting the extent of S glycosylation and thus viral transmission.

References

1. Zhang L, et al. Furin cleavage of the SARS-CoV-2 spike is modulated by O-glycosylation. Proc Natl Acad Sci U S A. 2021 Nov 23;118(47):e2109905118. doi: 10.1073/pnas.2109905118.
2. National Institutes of Health Press release, November 5, 2021.